Modeling metastatic progression from cross-sectional cancer genomics data.

MOTIVATION: Metastasis formation is a hallmark of cancer lethality. Yet, metastases are generally unobservable during their early stages of dissemination and spread to distant organs. Genomic datasets of matched primary tumors and metastases may offer insights into the underpinnings and the dynamics of metastasis formation. RESULTS: We present metMHN, a cancer progression model designed to deduce the joint progression of primary tumors and metastases using cross-sectional cancer genomics data. The model elucidates the statistical dependencies among genomic events, the formation of metastasis, and the clinical emergence of both primary tumors and their metastatic counterparts. metMHN enables the chronological reconstruction of mutational sequences and facilitates estimation of the timing of metastatic seeding. In a study of nearly 5000 lung adenocarcinomas, metMHN pinpointed TP53 and EGFR as mediators of metastasis formation. Furthermore, the study revealed that post-seeding adaptation is predominantly influenced by frequent copy number alterations. AVAILABILITY AND IMPLEMENTATION: All datasets and code are available on GitHub at https://github.com/cbg-ethz/metMHN.

Low-rank tensor methods for Markov chains with applications to tumor progression models.

Cancer progression can be described by continuous-time Markov chains whose state space grows exponentially in the number of somatic mutations. The age of a tumor at diagnosis is typically unknown. Therefore, the quantity of interest is the time-marginal distribution over all possible genotypes of tumors, defined as the transient distribution integrated over an exponentially distributed observation time. It can be obtained as the solution of a large linear system. However, the sheer size of this system renders classical solvers infeasible. We consider Markov chains whose transition rates are separable functions, allowing for an efficient low-rank tensor representation of the linear system's operator. Thus we can reduce the computational complexity from exponential to linear. We derive a convergent iterative method using low-rank formats whose result satisfies the normalization constraint of a distribution. We also perform numerical experiments illustrating that the marginal distribution is well approximated with low rank.

The multipole approach for EEG forward modeling using the finite element method.

For accurate EEG forward solutions, it is necessary to apply numerical methods that allow to take into account the realistic geometry of the subject's head. A commonly used method to solve this task is the finite element method (FEM). Different approaches have been developed to obtain EEG forward solutions for dipolar sources with the FEM. The St. Venant approach is frequently applied, since its high numerical accuracy and stability as well as its computational efficiency was demonstrated in multiple comparison studies. In this manuscript, we propose a variation of the St. Venant approach, the multipole approach, to improve the numerical accuracy of the St. Venant approach even further and to allow for the simulation of additional source scenarios, such as quadrupolar sources. Exploiting the multipole expansion of electric fields, we demonstrate that the newly proposed multipole approach achieves even higher numerical accuracies than the St. Venant approach in both multi-layer sphere and realistic head models. Additionally, we exemplarily show that the multipole approach allows to not only simulate dipolar but also quadrupolar sources.